Last update:
07-Jul-2004

Interleukin 18 (IL-18) was first described in 1989 as interferon γ (IFN-γ) inducing factor. It is a novel cytokine of the IL-1 family. IL-18 is an 18-kDa glycoprotein derived by cleavage of a 23-kDa precursor, pro-IL-18, by caspase 1. Pro-IL-18 is expressed in macrophages, dendritic cells, Kupffer cells, keratinocytes, chondrocytes, synovial fibroblasts and osteoblasts, while IL-18 receptor is present on naive T-lymphocytes, mature T-helper cells-type 1 (Th₁) cells, natural killer cells (NK), macrophages, neutrophils and chondrocytes. IL-18 acts via its receptor and signals through the IL-1 pathway which involves myeloid differentiation primary response protein, IL-1-receptor associated kinase, tumor necrosis factor α receptor-associated factor 6, transforming growth factor β activated kinase 1 and its binding protein, and activation of nuclear factor kB. IL-18 participates in both innate and acquired immunity. It induces Th1 maturation and activation of lymphocytes. IL-18 activates macrophages and induces cytokine release and nitric oxide production and it can enhance cell-to-cell interactions. It reduces chondrocyte proliferation, up-regulates nitric oxide synthase, stromelysin and cyclooxygenase 2 expression and enhances glycosaminoglycan release. In addition, IL-18 induces cytokine release and cytotoxicity from NK-cells and promotes angiogenesis from endothelial cells. Furthermore, it activates neutrophils while inhibiting osteoclast maturation. Regulation of IL-18 is mediated via IL-18 binding protein, a specific inhibitor for IL-18, which binds IL-18 with high affinity and neutralizes its function. It seems that IL-18 has a role in various rheumatic diseases. IL-18 mRNA and protein have been detected in rheumatoid arthritis (RA) synovial tissues while IL-18 receptor was also detected on synovial lymphocytes and macrophages. IL-18 seems to have a proinflammatory role in RA. It potentiates IL-12-induced IFN-γ production by T-cells in RA synovium. Overproduction of IL-18 has been described in adult Still’s disease and is possibly associated with the pathophysiology of the disease. IL-18 may play a role in various autoimmune diseases. Although IL-18 exhibits pleiotropic activities most data indicate that its proinflammatory effects predominate, particularly in inflammatory arthritis. Thus, IL-18 represents an attractive, novel therapeutic target.

Key words: Autoimmune diseases, Binding protein of interleukin 18, Biological activity of interleukin 18, Interleukin 18, Interleukin 18 receptor.